M. A. Eissenstat and J. D. Weaver (J. Org. Chem. 58(12), 3387-3390, (1993)) disclose the direct formation of a cyclic isourea from a diamine by reactiing cis-exo-2,3-diamino-5-norbornene and tetraethylorthocarbonate in the presence of acetic acid. (Scheme 1) ##STR2##
H. Kohn et. al. (J. Org. Chem. 42, 941, (1977)) disclose the formation of a cyclic isourea from a cyclic urea by reacting a N-acetyl cyclic urea and triethyloxonium tetrafluoroborate. (Scheme 2) ##STR3##
Copending commonly assigned U.S. patent application Ser. No. 08/230,562, filed Apr. 20, 1994, claims a process for the preparation of symmetrically or unsymmetrically nitrogen-disubstituted or -monosubstituted cyclic ureas having a broad range of hydroxy protecting groups for the diol as shown in Scheme 3. In that process, chromatographic separation of the unsubstituted and N-monosubstituted cyclic urea is required. ##STR4##
Copending commonly assigned U.S. patent application Ser. No. 08/197,630, filed Feb. 16, 1994, discloses a process for the preparation of symmetrically or unsymmetrically N,N'-disubstituted or N-monosubstituted cyclic ureas, having a broad range of hydroxyl protecting groups, via cyclization of an un- (R.sup.22 and R.sup.23 are H), mono- (one of R.sup.22 and R.sup.23 are H while the other is nonhydrogen) or disubstituted (both R.sup.22 and R.sup.23 are not hydrogen) linear diamine to the respective cyclic urea as shown in Scheme 4. The same application teaches that unsymmetrical N,N'-disubstituted cyclic ureas can be synthesized by reacting an N,N'-unsubstituted cyclic urea with less than two equivalents of an alkylating agent followed by chromatographic separation of the resulting mixture comprising of unsubstituted cyclic urea, N-monosubstituted cyclic urea, and symmetrical N,N'-disubstituted cyclic urea. Alkylation of the N-monosubstituted cyclic urea with an alkylating agent in the presence of strong base then provides unsymmetrical N,N'-disubstituted cyclic ureas. ##STR5## Also disclosed in U.S. Ser. No. 08/197,630 is the cyclization of a nitrogen-unsubstituted acetonide protected diaminodiol with CDI in methylene chloride, albeit in low yields. The yield of this cyclization could be improved by conducting it in refluxing tetrachloroethane. The cyclization of a nitrogen-unsubstituted bis-Mem protected diaminodiol was shown to occur in high yield. The use of acyclic diol protecting groups allowed for high cyclization yields but produced intermediates which were undesirable oils. These intermediates also lead to lower yields in subsequent steps of the process. The cyclization of a bis-Mem protected bis-monophenylhydrazinodiol (I) with phosgene to the corresponding cyclic urea (II) (as shown in Scheme 5) was disclosed in the same reference. ##STR6##
Although unsymmetrical N,N'-disubstituted cyclic ureas can be made by the methods described above, the products are often contaminated with symmetrical N,N'-disubstituted urea and yields are generally variable and low. Both procedures also give varying amounts of unalkylated cyclic urea.
Since unsymmetrical N,N'-disubstituted cyclic ureas are less crystalline and more soluble, they may prove advantageous in formulations and oral bioavailability over their symmetrical counterparts. In addition, unsymmetrical N,N'-disubstituted cyclic ureas may prove superior from a resistance standpoint; a major concern for HIV protease inhibitors. Clearly, a process which provides these compounds in good yield and purity is of considerable commercial value.
Despite the various methods for their preparation, there still exists a need for more efficient and cost-effective methods for the preparation of such unsymmetrical N,N'-disubstituted and N-monosubstituted cyclic urea HIV protease inhibitor compounds in high yields. The present invention provides improved processes for the synthesis of such compounds and processes for the synthesis of intermediates for their synthesis. This invention provides pure N-monoalkylated or N,N'-unsymmetrical dialkylated material in good yield without contamination by symmetrical byproducts or unalkylated urea.